1. Field of the Invention
The present invention relates to pharmaceutical compositions and uses thereof, and more particularly, to a pharmaceutical composition for treating hepatocellular carcinoma and use thereof.
2. Description of Associated Art
Hepatocellular carcinoma (HCC) is the fifth most commonly occurring cancer and the third most common cause of cancer-related deaths. Although the prognosis of HCC is poor, surgical resection and liver transplantation often have curative effects in patients.
Cancer cell migration is a critical process in tumor development and metastasis, and thus, anti-migration therapy is considered to be one of the approaches for cancer treatment. VEGF receptor signaling, such as VEGFR2 (KDR) signaling, has been implicated in HCC migration. The activation of downstream kinase, such as Src, FAK, and Rho-GTPase, induced by phosphorylated VEGFR2 results in remodeling of actin filaments and induction of migratory activity of tumor cells [1-4]. Previous studies have shown that knockdown of VEGFR suppresses HCC cell migration. The inhibition of VEGFR2 has been proposed as a novel therapeutic strategy for HCC patients. Various VEGFR2 kinase inhibitors such as sorafenib, sunitinib, and linifanib were developed and used in clinical trials.
Previous studies have discussed the pharmacophore modeling of different VEGFR2 inhibitors [5]. These inhibitors could be divided in two types, sunitinib-like or sorafenib-like, depending on the interacting hydrogen bonds. Sunitinib-like inhibitors form hydrogen bonds with residues of Asp1044, Cys917, and Asn921 near the protein surface. Sorafenib-like inhibitors interact with Asp1044, Cys917, and Glu883.
Recently, anti-HCC therapy with sorafenib has been approved by FDA [6, 7]. Sorafenib is a tyrosine kinase inhibitor and the mechanism thereof is to inhibit the activity of Raf protein in cell, and then to block RAF/MEK/ERK signaling pathway and to inhibit kinases of cell surface, which results in cell death and inhibits angiogenesis. However, there still exists some common side effects of the sorafenib formulation as chemotherapy, for example hand-foot syndrome, skin rash, hair loss, itching, redness, hypophosphatemia, weight loss, diarrhea, abdominal pain, nausea, vomiting, gastrointestinal bleeding, anemia, lymphocyte count decreased, thrombocytopenia, neutropenia, sensory neuropathy, tiredness, difficulty with breathing, pulmonary hemorrhage, pain and so on.
As known from the above, the therapies for HCC are quite limited. The conventional anticancer medicaments may affect the other functions of the subjects. Therefore, an efficient therapy for inhibiting HCC with decreased side effects which affect normal function is urged.